Significance: Pancreatic cancer is the 4th deadliest form of cancer in the U.S., with 95% of patients dying within 5-years of diagnosis. Currently, such patients have limited treatment options due to the lack of reliable methods for early detection. A key challenge faced by clinicians is to differentiate those patients with chronic pancreatitis from those with cancer, as the clinical presentation is often indistinguishable. Early identification of the ~30% of pancreatic cancer patients who present with localized, potentially resectable disease would remove a critical barrier to progress in the field by enabling the rapid therapy essential for reducing mortality. Here, we will design, develop, and pilot test a robust new tool for clinical decision-making to improve the accuracy of cancer detection in the pancreas. Approach: We will develop innovative optoelectronic diagnostic technology that is compatible with commercial platforms for endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) to enable accurate diagnosis of pancreatic neoplasia in vivo. Our team represents a partnership between engineers and clinicians from the University of Michigan (U-M), most of whom have collaborated productively on the foundational (pre)-clinical optical studies in the pancreas, including a successful in vivo feasibility study, with physicians as key participants in all project aims. In Aim #1 we will design, build, and verify the endoscopy-compatible optoelectronic microprobe technology using design specifications identified from preliminary studies. In Aim #2 we will pilot test the technology in clinically-simulated environments, includin optical testing on human pancreatic tissues, per robust clinical data acquisition protocols we established previously. Impact: Currently, for almost all patients, pancreatic cancer is a lethal disease. The potential impact of this project on clinical practice for this targeted cancer problem is large: improved clinical outcomes via early and accurate detection of those pancreatic cancer patients most amenable to therapy and cure. Successful outcomes in this project might apply to other forms of cancer, as well.